| Diabetes is a predisposition factor that imparts higher sensitivity to enhanced hepatotoxicity of several drugs and toxicants such as acetaminophen, bromobenzene, CCl4, thioacetamide (TA), etc. A recent prospective cohort study of 173,643 diabetic patients indicated that diabetic patients are at higher risk for acute liver failure. More and more drugs are being withdrawn after they cause unexpected fatalities in patients due to severe hepatotoxicity. These drugs reach the market after FDA approval because there is a little understanding about the mechanism of enhanced sensitivity of diabetics to hepatotoxicity. Therefore, understanding of the mechanism(s) of increased susceptibility of diabetics to hepatotoxicity is of clinical interest to predict hepatotoxic potential of antidiabetic drugs in preclinical toxicity testing.; Previous studies in our laboratory have established that a normally nonlethal dose of TA (300 mg/kg) causes 90% mortality in type 1 diabetic rats due to inhibited G0 to S phase cell cycle progression and inhibited tissue repair allowing liver injury to progress. On the other hand, diabetic rats exposed to a 10-fold lower dose of TA (30 mg/kg) exhibit delayed G0 to S phase cell cycle progression, delayed tissue repair, and delayed recovery from injury. However, it was not clear what are the molecular mechanisms that are responsible for impaired tissue repair in TA-treated diabetic rats. Therefore, the objective of this study was to investigate the dose-dependent modulation of the molecular events that orchestrate the liver tissue repair response to explain inhibited versus delayed G0 to S phase of cell cycle progression in the diabetic rats receiving 300 mg TA/kg versus 30 mg TA/kg, respectively. A comprehensive cDNA microarray analysis was used as a hypothesis-generating tool, which shortlisted cylin D1 and cathepsin signaling as potential targets of impaired liver tissue repair and progression of liver injury, respectively.; Administration of 300 mg TA/kg to non-diabetic rats led to increased expression of genes involved in cell cycle progression such as IGFBP-1, ras, and cyclin D1. Sufficient nuclear factor kappa-B (NF-kappaB)-DNA binding results in adequate expression of cyclin D1 that when coupled with cyclin dependent kinases, phosphorylates pRb, explaining the promptly stimulated cell division and tissue repair in the livers of rats challenged with TA. Stimulated tissue repair in TA-treated non-diabetic rats complements the increased expression of protease inhibitor (alpha-2-macroglobulin) because newly divided cells are known to overexpress protease inhibitors, thereby protecting the cells from hydrolytic destruction by proteases leaking out of necrotic cells. (Abstract shortened by UMI.)... |
